Abstract

In a genetic screen for enhancers and suppressors of a Frontotemporal Dementia related phenotype in Drosophila, we have identified two regulators of membrane traffic (Rab8 and OCRL1) that are known to physically interact. The physiological and cell biological consequence of the interaction between Rab8 and OCRL1 are as yet unknown. Rab8 is a small GTPase and a known regulator of membrane traffic at the Golgi and recycling endosome. Mutations in OCRL1 give rise to the neurodevelopmental condition Lowe Syndrome (LS). OCRL1 is a phosphoinositide phosphatase known to interact with many Rab proteins, endocytic proteins and actin cytoskeleton regulators to effect changes in membrane traffic. Due to issues of genetic redundancy, studies of Rab8 and OCRL1 have been hampered in model organisms to date. In Drosophila there are no redundancy issues for Rab8 or OCRL1. Using the advanced genetic toolbox of Drosophila we have identified mutants in Rab8 and OCRL1 and are now in a position to study: 1) the physiological, anatomical and cell biological consequence of loss of Rab8 function in neurons, 2) for the first time, study the cell biological, anatomical and physiological consequences of loss of OCRL1 function in neurons (and the whole organism), 3) the physiological role for the Rab8 interaction with OCRL1 in a whole organism. We have already observed dysregulation of TGF-beta and JNK/AP1 signaling at the larval neuromuscular synapse of Rab8 mutants. Our focus will be on the role of these two important proteins in regulation of membrane traffic at the synapse. This study will inform our understanding of membrane traffic in FTD and LS affected neurons.

Aims

In a genetic screen for enhancers and suppressors of a Frontotemporal Dementia related phenotype in Drosophila, we have identified two regulators of membrane traffic (Rab8 and OCRL1) that are known to physically interact. The physiological and cell biological consequence of the interaction between Rab8 and OCRL1 are as yet unknown. Rab8 is a small GTPase and a known regulator of membrane traffic at the Golgi and recycling endosome. Mutations in OCRL1 give rise to the neurodevelopmental condition Lowe Syndrome (LS). OCRL1 is a phosphoinositide phosphatase known to interact with many Rab proteins, endocytic proteins and actin cytoskeleton regulators to effect changes in membrane traffic. Due to issues of genetic redundancy, studies of Rab8 and OCRL1 have been hampered in model organisms to date. In Drosophila there are no redundancy issues for Rab8 or OCRL1. Using the advanced genetic toolbox of Drosophila we have identified mutants in Rab8 and OCRL1 and are now in a position to study:

1) the physiological, anatomical and cell biological consequence of loss of Rab8 function in neurons,
2) for the first time, study the cell biological, anatomical and physiological consequences of loss of OCRL1 function in neurons (and the whole organism),
3) the physiological role for the Rab8 interaction with OCRL1 in a whole organism. We have already observed dysregulation of TGF-beta and JNK/AP1 signaling at the larval neuromuscular synapse of Rab8 mutants.

Our focus will be on the role of these two important proteins in regulation of membrane traffic at the synapse. This study will inform our understanding of membrane traffic in FTD and LS affected neurons.